Phloretin Exerts Anti-Tuberculosis Activity and Suppresses Lung Inflammation

Molecules. 2017 Jan 22;22(1):183. doi: 10.3390/molecules22010183.


An increase in the prevalence of the drug-resistant Mycobacteria tuberculosis necessitates developing new types of anti-tuberculosis drugs. Here, we found that phloretin, a naturally-occurring flavonoid, has anti-mycobacterial effects on H37Rv, multi-drug-, and extensively drug-resistant clinical isolates, with minimum inhibitory concentrations of 182 and 364 μM, respectively. Since Mycobacteria cause lung inflammation that contributes to tuberculosis pathogenesis, anti-inflammatory effects of phloretin in interferon-γ-stimulated MRC-5 human lung fibroblasts and lipopolysaccharide (LPS)-stimulated dendritic cells were investigated. The release of interleukin (IL)-1β, IL-12, and tumor necrosis factor (TNF)-α was inhibited by phloretin. The mRNA levels of IL-1β, IL-6, IL-12, TNF-α, and matrix metalloproteinase-1, as well as p38 mitogen-activated protein kinase and extracellular signal-regulated kinase phosphorylation, were suppressed. A mouse in vivo study of LPS-stimulated lung inflammation showed that phloretin effectively suppressed the levels of TNF-α, IL-1β, and IL-6 in lung tissue with low cytotoxicity. Phloretin was found to bind M. tuberculosis β-ketoacyl acyl carrier protein synthase III (mtKASIII) with high affinity (7.221 × 10⁷ M-1); a binding model showed hydrogen bonding of A-ring 2'-hydroxy and B-ring 4-hydroxy groups of phloretin with Asn261 and Cys122 of mtKASIII, implying that mtKASIII can be a potential target protein. Therefore, phloretin can be a useful dietary natural product with anti-tuberculosis benefits.

Keywords: Mycobacterium tuberculosis; antibiotics; inflammation; natural compound; phloretin.

MeSH terms

  • 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / metabolism
  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Antitubercular Agents / pharmacology*
  • Binding Sites
  • Cell Line
  • Cytokines / metabolism*
  • Dendritic Cells / drug effects
  • Drug Resistance, Multiple, Bacterial
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Lipopolysaccharides
  • Lung / cytology
  • Lung / drug effects
  • Lung / pathology
  • MAP Kinase Signaling System / drug effects
  • Macrophages / drug effects
  • Mice
  • Mice, Inbred BALB C
  • Mycobacterium tuberculosis / drug effects*
  • Phloretin / pharmacology*
  • Pneumonia / drug therapy*
  • Pneumonia / microbiology
  • Protein Binding / physiology
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Anti-Inflammatory Agents
  • Antitubercular Agents
  • Cytokines
  • Lipopolysaccharides
  • 3-ketoacyl-acyl carrier protein synthase III
  • 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Phloretin